Tongue measurements and pharyngeal residue in amyotrophic lateral sclerosis.

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This study aimed to analyze the relationship of measurable characteristics of the tongue in patients with amyotrophic lateral sclerosis (ALS) and the accumulation of residue after swallowing in an area located just after the tongue. enter image description here This accumulation of residue provides a sensation of bolus stuck in the throat and increases the risk of weight loss, choking and pulmonary complications.

Twenty-one ALS patients were assessed for tongue pressure, tongue endurance, tongue thickness and residue after swallowing of the 10 ml of moderately thickened consistency. This study concluded that all tongue measurements were low in ALS patients with and without residue.

Therefore, these tongue measurements are not good predictors of vallecular residue in the tested volume and food consistency.

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SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron. It inhibits reabsorption of glucose in the kidney and therefore lower blood sugar.

DPP-4 inhibitors increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) on new-onset cognitive dysfunction in type 2 diabetes mellitus remain unknown.

This study aimed to evaluate the effects of the two novel antidiabetic agents on cognitive dysfunction by comparing the rates of dementia between SGLT2I and DPP4I users.

This was a population-based cohort study of type 2 diabetes mellitus patients treated with SGLT2I and DPP4I between January 1, 2015 and December 31, 2019 in Hong Kong. Exclusion criteria were <1-month exposure or exposure to both medication classes, or prior diagnosis of dementia or major neurological/psychiatric diseases. * Primary outcomes were new-onset dementia, Alzheimer's, and Parkinson's. * Secondary outcomes were all-cause, cardiovascular, and cerebrovascular mortality.

Results: A total of 13,276 SGLT2I and 36,544 DPP4I users were studied, SGLT2I users had lower incidences of dementia , Alzheimer's, Parkinson's disease, all-cause, cerebrovascular, and cardiovascular mortality.

In conclusions the use of SGLT2I is associated with lower risks of dementia, Parkinson's disease, and cerebrovascular mortality compared with DPP4I use after 1:2 ratio propensity score matching.

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This study investigated the criterion and construct validity of a novel, acoustic-based framework composed of five key components of motor control: Coordination, Consistency, Speed, Precision, and Rate.

Acoustic and kinematic analyses were performed on audio recordings from 22 subjects with amyotrophic lateral sclerosis during a sequential motion rate task. Perceptual analyses were completed by two licensed speech-language pathologists, who rated each subject's speech on the five framework components and their overall severity. Analytical and clinical validity were assessed by comparing performance on the acoustic features to their kinematic correlates and to clinician ratings of the five components, respectively.

Divergent validity of the acoustic-based framework was then assessed by comparing performance on each pair of acoustic features to determine whether the features represent distinct articulatory constructs. Bivariate correlations and partial correlations with severity as a covariate were conducted for each comparison.

Results revealed moderate-to-strong analytical validity for every acoustic feature, both with and without controlling for severity, and moderate-to-strong clinical validity for all acoustic features except Coordination, without controlling for severity. When severity was included as a covariate, the strong associations for Speed and Precision became weak.

Divergent validity was supported by weak-to-moderate pairwise associations between all acoustic features except Speed (second-formant [F2] slope of consonant transition) and Precision (between-consonant variability in F2 slope).

This study demonstrated that the acoustic-based framework has potential as an objective, valid, and clinically useful tool for profiling articulatory deficits in individuals with speech motor disorders. The findings also suggest that compared to clinician ratings, instrumental measures are more sensitive to subtle differences in articulatory function. With further research, this framework could provide more accurate and reliable characterizations of articulatory impairment, which may eventually increase clinical confidence in the diagnosis and treatment of patients with different articulatory phenotypes.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Mild Cognitive Impairment (MCI) is fraught with high false positive diagnostic errors. The high rate of false positive diagnosis hampers attempts to identify reliable and valid biomarkers for MCI.

Recent research suggests that aberrant functional neurocircuitries emerge prior to significant cognitive deficits. The aim of the present study was to examine this in clinically confirmed multi-domain amnestic-MCI (mdaMCI) using an established, multi-time point, methodology for minimizing false positive diagnosis.

Structural and resting-state functional MRI data were acquired in healthy controls (HC, n=24), clinically-confirmed multi-domain amnestic-MCI (mdaMCI, n=14) and mild Alzheimer's Dementia (mAD, n=6).

Group differences in cortical thickness, hippocampal volume and functional connectivity were investigated. Hippocampal subvolumes differentiated mAD from HC and mdaMCI.

Functional decoupling of fronto-temporal networks implicated in memory and executive function differentiated HC and mdaMCI.

Decreased functional connectivity in these networks was associated with poorer cognitive performance scores.

Preliminary findings suggest the large-scale decoupling of fronto-temporal networks associated with cognitive decline precedes measurable structural neurodegeneration in clinically confirmed MCI and may represent a potential biomarker for disease progression.

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Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide, but given the lack of clinical efficacy of amyloid β inhibitors, this is increasingly disputed.

Yet neprilysin-deficient knockout mice exhibit both Alzheimer's-like behavioral alteration and beta-amyloid deposition in the brain. Since neprilysin is considered to be the step limiting the rate of degradation of beta-amyloid, it has been considered as a potential therapeutic target.

Scientists have previously shown that somatostatin, a neuropeptide, regulates Aβ42 levels in the brain via upregulation of neprilysin. Somatostatin mRNA levels are significantly decreased with aging, especially in Alzheimer's disease. This suggests that the aging-induced downregulation of somatostatin expression may be a trigger for amyloid β peptide pathology in late-onset Alzheimer's disease.

However, the mechanism by which somatostatin signaling regulates neprilysin activity remains unclear. In the present study, the authors used in vitro and in vivo experimental paradigms to identify α-endosulfine (ENSA) as a negative regulator of neprilysin activity downstream of somatostatin signaling.

In vitro and in vivo experiments revealed that neprilysin degrades α-endosulfine (ENSA) as a substrate, suggesting that neprilysin and α-endosulfine (ENSA) form a negative feedback loop. This hypothesis is based on the fact that opioids and substance P, cell-specific ligands in monocytes and bone marrow cells, respectively, regulate neprilysin via a feedback mechanism. It is possible that amyloid β peptide and α-endosulfine (ENSA) compete against each other in neprilysin-mediated degradation, additively exacerbating this feedback loop and inducing a vicious cycle.

A selective KATP channel agonist such as diazoxide (Dz) could serve as a beneficial approach to break this vicious cycle since diazoxide is sometimes used as a drug for antihypertensive and hypoglycemic properties, and has the potential in the preclinical setting. 'improve amyloid β peptide pathology and behavioral abnormalities in Alzheimer's disease.

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension. Diazoxide also inhibits insulin secretion by opening the ATP-sensitive potassium channel of pancreatic beta cells;

The mechanism by which diazoxide (Dz) attenuated amyloid peptide plaque deposition was not clear, however. Their results indicate that diazoxide (Dz) reduced amyloid deposition in AppNL-F mice via the regulation of neprilysin activity in the anterior cortex and the hippocampus. This regional selectivity of the action of neprilysin by diazoxide (Dz) may depend on the dopaminergic system in the brain.

The authors have therefore demonstrated a new preventive approach at the preclinical stage of Alzheimer's disease based on the function of α-endosulfine (ENSA). This negative regulator of neprilysin and of the KATP channel could be a new therapeutic target for lowering the amyloid β peptide.

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This study evaluates the incidence, prevalence and survival trends of motor neurone disease (MND) in Northern Ireland from 2015 to 2019.

A capture-recapture analysis was performed using five independent data sources. Incidence and prevalence rates were standardized to the European Standard Population. Survival outcomes were analysed using Kaplan-Meier curves and Cox regression analysis.

Amongst 254 total cases of MND. Age standardized incidence of captured cases was 3.12 per 100,000 while in 2006 it was 1.4 per 100,000. Of identified cases, 133 (52.4%) were male; 94.5% had amyotrophic lateral sclerosis; median age of onset was 67 years; median time to diagnosis was 12 months; survival from diagnosis was 12 months.

25 people (9.8%) reported a family history of MND or frontotemporal dementia; and a known MND-associated genetic mutation was identified in 7.9% of total cases, of which the most common was C9orf72 (5.7% of all patients).

Factors associated with improved survival were younger age at onset, longer time to diagnosis, attendance at regional MND clinic, and initial neurology presentation as outpatient (all p < 0.001).

Conclusion: The incidence and prevalence of MND in Northern Ireland has increased over the last 10 years, in line with increasing rates reported from other European countries. Improved survival was associated with younger age at onset, longer time to diagnosis, attendance at a regional MND clinic and outpatient presentation to a Neurology Department.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Objectives: Dementia of the Alzheimer's type (DAT) is the most common chronic neurodegenerative disease. At present, the pathogenesis of Alzheimer's disease is not completely clear, and there are no drugs that can cure the disease. Once an individual is diagnosed with Alzheimer's disease, the survival time is only 3 to 9 years.

Therefore, there is an urgent need to determine the etiology of Alzheimer's disease and the associated influencing factors to find a breakthrough in the treatment of DAT.

Methods: We studied the relationship between polymorphisms in several genes (including BIN1 and APOE) and Alzheimer's disease susceptibility and the effects of sex differences on Alzheimer's disease.

Our study included 137 patients with Alzheimer's disease and 509 healthy controls (HCs). Results: The APOE rs429358 polymorphism CC and CT genotypes were associated with an increased risk of Alzheimer's disease in women.

We found a significant association between APOE ε4 and Alzheimer's disease. The frequency of the ε4 allele in the Alzheimer's disease group (15.5%) was higher than that in the HC group (8.7%). The BIN1 rs7561528 polymorphism was associated with a decreased risk of DAT in men.

Conclusions: APOE gene rs429358 and BIN1 gene 7561528 genes may affect the susceptibility to Alzheimer's disease in a Chinese Han population.

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Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions.

Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS.

Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions.

We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])).

Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25.

These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.

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Here we will discuss about two recent studies about the relation between protocatechuic acid and Alzheimer's disease.

Diet appears to be have some relation with the progression of Alzheimer's disease, maybe related to the gut microbiome. There is a clear relation between gut's microbiome and Alzheimer's disease which was formalized in Braak's stages.

The aims of the first study were to detect the main anthocyanins of blueberry extract; then to verify the protective effects of anthocyanin-rich blueberry extract on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid, a major metabolite of blueberry extract, for promoting autophagy and thus playing a neuroprotective role.

Protocatechuic acid is a type of phenolic acid increasing bringing plants resistance against fungus. It is a major metabolite of antioxidant polyphenols found in green tea. It has mixed effects on normal and cancer cells in in vitro and in vivo studies. Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in protocatechuic acid (630±36 mg/kg). enter image description here

Protocatechuic acid is regarded as an active component in traditional Chinese herbal medicine. For example the dried and mature fruits of the Zingiberaceae plant Alpinia oxyphylla Miq, is a choice in traditional Chinese medicine to treat Alzheimer's disease.

Recent studies have demonstrated its potent activities in modulating multiple signaling pathways associated with β-amyloid deposition, tau protein phosphorylation, chronic inflammation, oxidative stress.

In this study mice models of Alzheimer's disease (APP/PS1) were given 150 mg/kg blueberry extract daily for 16 working days. The mice were then sacrificed and morphology of neurons was observed under transmission electron microscope and autophagy-related proteins were detected.

Protocatechuic acid also promoted autophagy of neurons and the mechanism was mainly involved in increasing autophagosome degradation.

Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after blueberry extract treatment. In vitro, Aβ25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by protocatechuic acid.

Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by protocatechuic acid.

Yet it seems unlikely that any chemical coumpound would dramatically improve Alzheimer's disease in a few weeks and we all know that few results like that are credible. However other recent studies have hinted at similar results.

Protocatechuic acid is a dihydroxybenzoic acid with is a precursor of some insecticides and neurotransmitters like catecholamines, so it is indeed a potent and possibly dangerous drug.

In the treatment of Alzheimer's disease, it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation.

The aim of this other study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum.

Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking.

Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively.

The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of Alzheimer's disease.

Neuropathological evidence of body-first vs. brain-first Lewy body disease.

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In most neurodegenerative diseases there are contradictory explanations of where the disease strikes and how it progresses. For a majority of scientists it begins somewhere in the brain, while for a minority it appears in guts, mucous membranes or muscles.

Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (LBD), a less agressive form of the Parkinson's disease.

The Braak staging system is based on the idea that Lewy pathology starts in the olfactory bulb and enteric nervous system, and invades the brain via the vagus nerve. Alternative hypotheses propose that Lewy pathology does not start in the gut but inside the central nervous system (CNS), or possibly via an isolated olfactory entry route followed by intra-cerebral propagation.

A potential problem with both the Braak and DLB consortium staging systems is that relatively little emphasis is put on the magnitude of Lewy pathology in a given region. Assignment of a case to a specific category or stage is based mainly on the spatial distribution of pathology. Thus, two patients who display Lewy pathology in the same anatomical regions, but who have quite different levels of pathology in those regions, will nevertheless be labeled with the same Braak or DLB consortium stage.

A recent paper analyzed 124 Lewy pathology-positive post mortem cases in a population-based sample of subjects aged over 85 years (Raunio et al., 2019). The authors showed that approximately two-thirds of the cases conformed to a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon.

The remaining one-third showed an amygdala-centered pattern with a peak of pathology in the “center of the brain”, including the amygdala, entorhinal cortex, and SN, and then relatively less pathology in the lower brainstem, spinal intermediolateral column (IML), and also in neocortical regions.

Here, the authors use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.

In summary, caudo-rostral and amygdala-centered profiles of Lewy pathology seem to be the two most common patterns seen in post mortem studies. In cases with a low global burden of Lewy pathology, thought to be early prodromal disease, the patterns are particularly clear. Therefore, it seems likely that patients with Lewy body disorders most commonly evolve from one of these two initial conditions.

Using in vivo, multi-modal imaging, it was recently shown that patients with prodromal and de novo PD can be divided into two clusters compatible with brain-first and body-first etiology.

In this paper the authors argue that body-first patients, in whom the sympathetic system degenerates before the dopamine system, are equivalent to post mortem cases with a caudo-rostral distribution of Lewy pathology. In early caudo-rostral cases, the autonomic structures display more pathology than the substantia nigra and limbic structures.

In contrast, brain-first patients show dopaminergic degeneration before sympathetic denervation. The scientists remarked that these patients are equivalent to post mortem cases with an amygdala-centered distribution of Lewy pathology, where limbic structures and the nigra show more pathology than do the autonomic structures.

This hypothesis could be tested in future studies, especially once a PET tracer targeting alpha-synuclein becomes available.

This line of reasoning suggests that the gut-first hypothesis posed by Braak and colleagues is only valid for that part of LBD patients, which the authors refer to as the body-first subtype.

Importantly, if the Lewy pathology in the remaining part of patients truly originates inside the brain or olfactory bulb and generally shows a top-down direction of propagation, it will be much more difficult to identify brain-first LBD at the prodromal stage.

These patients will generally not develop the most recognizable prodromal symptoms such as RBD and autonomic dysfunction until after parkinsonism or dementia have manifested.

If correct, this further emphasizes the importance of developing robust biomarkers in body fluids to detect brain-first LBD at an early stage, where neuroprotective treatments will be most effective.

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